Electrochemical carbon–carbon coupling with enhanced activity and racemate stereoselectivity by microenvironment regulation

Enzymes are characteristic of catalytic efficiency and specificity by maneuvering multiple components in concert at a confined nanoscale space. However, achieving such a configuration in artificial catalysts remains challenging. Herein, we report a microenvironment regulation strategy by modifying carbon paper with hexadecyltrimethylammonium cations, delivering electrochemical carbon–carbon coupling of benzaldehyde with enhanced activity and racemate stereoselectivity. The modified electrode–electrolyte interface creates an optimal microenvironment for electrocatalysis—it engenders dipolar interaction with the reaction intermediate, giving a 2.2-fold higher reaction rate (from 0.13 to 0.28 mmol h−1 cm−2); Moreover, it repels interfacial water and modulates the conformational specificity of reaction intermediate by facilitating intermolecular hydrogen bonding, affording 2.5-fold higher diastereomeric ratio of racemate to mesomer (from 0.73 to 1.82). We expect that the microenvironment regulation strategy will lead to the advanced design of electrode–electrolyte interface for enhanced activity and (stereo)selectivity that mimics enzymes.

authors address the following technical issues： 1.For acid-treated and untreated carbon paper, the contact angle (CA) experiment should be provided to prove the changes in interfacial hydrophobicity.2. Whether the results of CA experiments were measured at the same moment during the experimental process?It's well-known that the contact angle will change with the measurement time.3. Tafel experiments for CP and CP-CTAB require i-R correction to obtain the intrinsic electrochemical kinetic features.4. It's noticed that in the ATR-SERIRS measurements, Carbon ECP600JD was used instead of CP for the experiment.It is necessary to compare the difference in electrocatalytic performance of Carbon ECP600JD and Carbon ECP600JD-CTAB in the H cell and compare them with the electrocatalytic systems with CP and CP-CTAB. 5.The qualitative and quantification method of coupling products of furfural and acetophenone should be provided given that their diastereomers are not commercially available.6.Some typo issues, such as in Supplementary Tables 1-8, the units of Rs and Rct should be Ω•cm2 rather than Ω•cm-2.

Response letter
General response: We thank the reviewers for their valuable comments and appreciate the editor for giving us the opportunity to revise the manuscript; a series of additional experiments have been performed to enable us to fully address the comments raised by the reviewers.Please find the point-by-point response below, the revised Manuscript and Supplementary Information with the changes highlighted in yellow.

Response to Reviewer #1:
This manuscript describes a microenvironment regulation strategy which not only enhanced the reaction rate of electroreductive C-C coupling of benzaldehyde but also regulated the stereoselectivity of hydrobenzoin products.The authors showed the establishment of a confined microenvironment consisting of ordered CTAB molecules at electrode/electrolyte interface under reaction conditions.Based on this knowledge and substantial evidences, the authors convincingly demonstrated that the enhanced dipolar interactions contributed to the promoted activity, and the hydrophobic microenvironment contributed to the regulated stereoselectivity.Overall, this work provides a very systematic understanding of the structure-activity relationship for the microenvironment regulation in electrocatalysis, and a novel and fascinating perspective on the stereoselectivity regulation of C-C coupling products.In my opinion, this work is insightful for the rational design of microenvironment regulation strategy beyond biomass electroreduction.Therefore, I recommend the publication of this manuscript in Nat.Commun.upon minor revisions.Response: We thank the reviewer for providing the valuable references.4 additional papers on the microenvironment strategy have been added in the introduction section.
To clearly present these results, we revised the Manuscript as follows: "These successful examples show the potential of microenvironmental regulation to enhance catalytic activity.In addition, this strategy exhibits a wide range of applications, 10,11 including electrocatalytic reductions (e.g., hydrogen evolution reaction (HER) 12 , oxygen reduction reaction (ORR) 13 and carbon dioxide reduction reaction (CO2RR) 14 ) and oxidations (e.g., oxygen evolution reaction (OER) 15  Response: According to these insightful suggestions, the effects of different alkali cations on the catalytic reaction were performed.Li2SO4, K2SO4 and Cs2SO4 at the same concentration (0.5 M; due to solubility limitation, the actual concentration of Li2SO4 was about 0.25 M) were used, respectively, as substitutes for Na2SO4 electrolyte.
Then, electrochemical pinacol coupling was conducted with or without CTAB.The catalytic results are shown in the revised Supplementary Fig. 37.
Without CTAB, the reaction rate followed the trend of Li + < Na + < K + ≈ Cs + .The dr of hydrobenzoin followed the trend of Na + ≈ K + < Li + < Cs + .These results indicate that different cations indeed affected the activity and dr, probably induced by adsorption at electrode interface.However, the increased extent of reaction rate was not as significant as that using CTAB (K + and Cs + : 0.18 mmol h -1 cm -2 ; CTAB: 0.28 mmol h - 1 cm -2 ), suggesting the important role of CTAB for the enhanced activity.Regarding dr value, the addition of Cs + promoted dr (2.14) even higher than the addition of CTAB (1.82), while other cations did not exhibit a significant effect.These results can be explained by the specific adsorption of Cs + at electrode interface to repel the interfacial water, as evidenced by the desorption peak at −0.8 V versus Ag/AgCl in the LSV curve (the revised Supplementary Fig. 37a, b).We tentatively proposed that Cs + may display a similar effect as CTA + , that is, creating a hydrophobic microenvironment at electrode−electrolyte interface.
When CTAB was introduced into the electrolyte involving Li + , Na + , K + or Cs + cations, the reaction rate exhibited an order of Li + < Na + ≈ K + < Cs + but with insignificant difference.The dr of hydrobenzoin was basically unchanged between different alkali cations.These results indicate that the specific adsorption of CTA + was more favorable compared with that of other cations we tested.

Based on the above discussion, we revised the Manuscript and Supplementary
Information as follows: 1.The discussion on alkali cations on the catalytic performance has been added in the revised Manuscript: "Recently, alkali cation was reported to greatly modulate the microenvironment at electrode−electrolyte interface, affecting the catalytic performance 46 .Hence, electrocatalytic pinacol coupling was further conducted in the presence of different alkali cations with or without CTAB, aiming to examine if CTAB exhibits a unique effect on the catalytic performance.When CTAB was absent, different cations indeed affected the activity but with less significant extent compared with CTAB (Supplementary Fig. 36).Meanwhile, the addition of Cs + promoted dr value with higher extent compared with the addition of CTAB, while other cations did not exhibit a significant effect.The effect of Cs + on catalytic performance is worth further exploration, which is beyond the scope of this work.When CTAB was introduced, the activity and dr of hydrobenzoin were basically unchanged in the presence of different alkali cations, indicating that the specific adsorption of CTA + was more favorable under our reaction conditions.Collectively, these results suggest that CTAB serves as a unique molecule for microenvironment regulation in our study (see Supplementary Note 6 for more discussion."(Please see Page 16 in the revised Manuscript) 2. The discussion of the effect of alkali cations on catalytic performance was presented in the revised Supplementary Note 6 in the Supplementary Information: Li2SO4, K2SO4 and Cs2SO4 at the same concentration (0.5 M; due to solubility limitation, the actual concentration of Li2SO4 was about 0.25 M) were used, respectively, as substitutes for Na2SO4 electrolyte.Then, electrochemical pinacol coupling was conducted with or without CTAB.The catalytic results are shown in the revised Supplementary Fig. 36.
Without CTAB, the reaction rate followed the trend of Li + < Na + < K + ≈ Cs + .The dr of hydrobenzoin followed the trend of Na + ≈ K + < Li + < Cs + .These results indicate that different cations indeed affected the activity and dr, probably induced by adsorption at electrode interface.However, the increased extent of reaction rate was not as significant as that using CTAB (K + and Cs + : 0.18 mmol h -1 cm -2 ; CTAB: 0.28 mmol h - 1 cm -2 ), suggesting the important role of CTAB for the enhanced activity.Regarding dr value, the addition of Cs + promoted dr (2.14) even higher than the addition of CTAB (1.82), while other cations did not exhibit a significant effect.These results can be explained by the specific adsorption of Cs + at electrode interface to repel the interfacial water, as evidenced by the desorption peak at −0.8 V versus Ag/AgCl in the LSV curve (the revised Supplementary Fig. 36a, b).We tentatively proposed that Cs + may display a similar effect as CTA + , that is, creating a hydrophobic microenvironment at electrode−electrolyte interface.
When CTAB was introduced into the electrolyte involving Li + , Na + , K + or Cs + cations, the reaction rate exhibited an order of Li + < Na + ≈ K + < Cs + but with insignificant difference.The dr of hydrobenzoin was basically unchanged between different alkali cations.These results indicate that the specific adsorption of CTA + was more favorable compared with that of other cations we tested.

Collectively, the above experiments indicate that CTAB serves as a unique molecule
for microenvironment regulation during electrochemical pinacol coupling reaction.In addition, the varied dr induced by Cs + is worth further exploration, and its in-depth investigation is beyond the scope of this manuscript."(Please see Page 7 in the revised Supplementary Information) Comment 4: As far as I know, the stereoisomers of electroreductive product of furfural and acetophenone are not available to be purchased.Hence, I wonder how you distinguish between these two isomers of the products of furfural and acetophenone.
Response: We appreciated the reviewer for providing this critical suggestion.The dimers of furfural and acetophenone are indeed not commercially available.According to the report of Kim and his coworker (J.Org.Chem.1998, 63, 5235-5239), the stereoisomers of the reduction coupling products of aromatic aldehydes and ketones could be qualitatively and quantitively identified by 1 H-NMR.It was demonstrated that the chemical shift of directly-bonded hydrogen atoms (for aldehydes) or hydrogen atoms on methyl group (for ketones) connected to the chiral center on the mesomers was 0.05~0.10ppm higher than that of racemate.
Our experiment results were consistent with the above observations.We carried out bulk electrolysis experiments with furfural or acetophenone as the substrates.Then, 0.9 mL of the reaction solution was abstracted with the addition of 0.1 mL of D2O for 1 H-NMR analysis.The 1 H-NMR spectra were presented in revised Supplementary Figs.3-4: Revised Supplementary Fig. 3 1 H-NMR spectrum of the reaction after bulk electrolysis of furfural.The reaction was conducted at -1.4 V vs. Ag/AgCl.The spectrum is consistent with that in the previous report 22 .
Revised Supplementary Fig. 6 HPLC spectra of the reaction products.HPLC spectra of the reaction products with a benzaldehyde, b furfural and c acetophenone.
The reactions were carried out in 0.5 M Na2SO4 electrolyte containing 25 mM substate.

Revised Supplementary Fig. 5 Comparison of dr value determined by HPLC and
1 H-NMR.Bulk electrolysis of furfural and acetophenone were performed, and the products were subjected to HPLC and 1 H-NMR analysis.

Information as follows:
1.The analysis details of 1 H-NMR have been provided in Methods of the revised Manuscript: "… Benzaldehyde, furfural, acetophenone and their products were quantitatively analyzed using a C18 column (4.6 mm×250 mm, 5μm).For benzaldehyde and acetophenone, the column was operated at 35 o C with a flow rate of 1.0 mL min -1 using CH3CN-H2O mixture (40%:60%, v/v) as the mobile phase.For furfural, the column was operated at 45 o C with a flow rate of 0.8 mL min -1 using a binary gradient pumping method.The binary gradient pumping method was set as: the CH3CN fraction in CH3CN-water mixture (v/v) was kept at 15% (0~3.78 min), increased from 15% to 60% (3.78~11.28min), kept at 60% (11.28~12.78min), decreased from 60% to 15% (12.78~15 min), and kept at 15% (15~18 min).The isomers of hydrobenzoin were purchased and identified.The dimer of furfural and acetophenone were quantified by setting the response coefficient of dimer to twice of that for the corresponding alcohol, which was adopted by Xu's report 52 .Due to the commercial unavailability of the coupling products of furfural and acetophenone, 1 H-NMR experiments were carried out to qualitatively identify stereoisomers, see Supplementary Figs 3-6.…" (Please see Page 20 in the revised Manuscript) 2. We revised the caption of Supplementary Fig. 5 in Supplementary Information: "According to the report of Kim and coworker 23 , the stereoisomers of the reduction coupling products of aromatic aldehydes and ketones could be qualitatively and quantitively identified by 1 H-NMR.It was demonstrated that the chemical shift of directly-bonded hydrogen atoms (for aldehydes) or hydrogen atoms on methyl group (for ketones) connected to the chiral center on the mesomers was 0.05~0.10ppm higher than that of racemate.
Hence, we measured the dr value of coupling products of furfural and acetophenone by 1 H-NMR based on the qualitative method shown above.The results show a good consistent with the results measured by HPLC.Therefore, it is safe to qualitatively identify the stereoisomers of the coupling products from furfural and acetophenone by Response: We thank the reviewer for point out the mistake in Supplementary Fig. 24d.
We have corrected it in revised Supplementary Fig. 27d accordingly.(Please see Page

Comment 1 :
In the introduction section, the statement: "this strategy was limited to a handful electrocatalytic reactions including hydrogen, oxygen and CO2 reductions."requires additional references (Chem 2022, 8, 1-15 for electrocatalytic oxygen evolution reaction; Angew Chem Int Ed 2022, 61, e202113362 for glycerol electrooxidation) about the microenvironment strategy for electrooxidation reaction to demonstrate the universality of this strategy (National Sci.Rev. and glycerol electrooxidation (GOR) 16 )."(Please see Page 2 in the revised Manuscript) Comment 2: A related work on stereoselectivity regulation in electrocatalytic aromatic aldehyde C-C coupling was mentioned by a literature of Kashimura et al. (Electrochimica Acta 2005, 51, 14-22).Although it did not provide any opinion on the structure-activity relationship of stereoselectivity regulation, I think this work should be cited in the introduction section.Response: We thank the reviewer for providing the valuable paper, which has been added in the introduction section.To clearly present these results, we revised the Manuscript as follows: "However, stereoselectivity regulation of electrocatalytic aromatic aldehyde C−C coupling was rarely studied 17 , with lacking of in-depth understanding of the structureactivity correlation.Meanwhile, microenvironment regulation has never been explored for …" (Please see Page 2 in the revised Manuscript) Comment 3: The cation strategy was universally reported in electrocatalytic CO2 reduction reaction (CO2RR) for the different microenvironment created by local field of hydrated cations.Xu et al. proposed the CO2RR activity was not related to the concentration of OH-, but rather to that of cations (Angew.Chem.Int.Ed. 2020, 59, 4464-4469).Thoi et al. also discovered that introduced CTAB molecules had different effects on CO2RR activity in the electrolyte containing different cations (ACS Catal.2020, 10, 9907-9914).Hence, I am curious whether the supporting electrolytes with different cations will have similar effects on the reported system in this manuscript, and how these cations will interact with the introduced CTA + cations.
Collectively, the above experiments indicate CTAB serves as a unique molecule for microenvironment regulation during electrochemical pinacol coupling reaction.In addition, the varied dr induced by Cs + is worth further exploration, and its in-depth investigation is beyond the scope of this manuscript.Revised Supplementary Fig. 36 Investigation of different alkali cations on affecting electrochemical pinacol C−C coupling reaction.a LSV plot and b corresponding enlarged region.Reaction conditions: electrolyte contains 0.5 M Cs2SO4 and 50 mM benzaldehyde, with or without CTAB.Reaction rate of hydrobenzoin in the electrolyte with 0.5 M different alkali cations (Li + , Na + , K + or Cs + ) at −1.4 V versus Ag/AgCl c without or d with 1 mM CTAB.Stereoselectivity of hydrobenzoin in the electrolyte with different cations at −1.4 V versus Ag/AgCl e without or f with 1 mM CTAB.Error bars correspond to the standard deviation of three independent measurements.
1 H-NMR, and to quantitatively measured the reaction results by HPLC." (Please see Page 12 in the revised Supplementary Information) Comment 5: Supplementary Fig. 24d is not consistent with the main text, in which the stereoselectivity of acid-treated CP with CTAB should be similar with that of nonacid-treated CP with CTAB as the manuscript mentioned.